The present invention is related to new oral pharmaceutical preparations especially for use in the treatment and prophylaxis of gastrointestinal disorders associated with the use of Non Steroidal Antiinflammatory Drugs (NSAIDs). The present preparations comprise an acid susceptible proton pump inhibitor in combination with one or more NSAID(s) in a new fixed unit dosage form, especially a tableted dosage form. Furthermore, the present invention refers to a method for the manufacture of such preparations and the use of such preparations in medicine.
NASAIDs including acetyl salicyclic acid are among the most commonly prescribed and used drugs world-wide. Despite the therapeutic benefits of NSAIDs, their use is frequently limited by an increased risk of gastrointestinal side-effects, mainly upper gastrointestinal side-effects like peptic ulceration and dyspeptic symptoms.
The relative risk of developing a gastric ulcer during NSAID treatment is increased by a factor 40-50, and the relative risk of developing a duodenal ulcer is increased by a factor 8-10 (McCarty DM. Gastroenterology 1989;96:662). The relative risk of developing an ulcer complication like bleeding and perforation of the stomach is increased by a factor 1.5-5 (Hawkey C. BMJ 1990;300:278). Further dyspeptic symptoms are experienced in 30-60% of those on NSAID treatment (Larkai En.AmJGas 1987;82:1153).
In UK, NSAIDs account for 25% of all reports of adverse drug reactions received by the authorities, and the corresponding figure is 21% in USA. Therefore, therapies which avoid gastrointestinal side-effect caused by NSAIDs is requested.
Attempts to modify the NSAID structure in order to prevent such side-effects have so far been less successful. The most promising solution to the problem of healing and preventing NSAID associated upper gastrointestinal problems like ulcers and dyspeptic symptoms in patients with a need for continuous NSAID treatment is to combine the NSAID treatment with an anti-ulcer drug approved for the healing and/or prophylaxis of NSAID associated gastrointestinal side-effects such as prostaglandin analogues, H2-receptor antagonists or proton pump inhibitors.
Established risk factors for developing NSAID associated upper gastrointestinal side-effects and complications are for instance high age, previous peptic ulcer and/or bleeding, high dose of NSAID, co-therapy with steroids, and co-therapy with anticoagulants. This means, that for example fragile and elderly patients tolerating a complication like bleeding or perforation badly, should receive prophylactic treatment in connection with their NSAID treatment.
NSAIDs are mainly used for the treatment of chronic diseases like rheumatoid arthritis and osteoarthritis, which are most often seen in the elderly population. Compliance is especially important in elderly and fragile patients, who have the highest risk of developing a life-threatening complication to NSAID treatment like bleeding or perforation. It is known that 50% of all peptic ulcer deaths occur in NSAID users and that 68% of these are  greater than 75 years old (Catford:Health Trends 1986;18:38). This is confirmed in another study concluding, that NSAID-related deaths occur primarily in those  greater than 75 years of age. (Guess. J Clin Epidemiol 1988;41:35). The importance of compliance is further supported by the finding, that a majority of peptic ulcers associated with NSAID treatment are asymptomatic until the event.
Omeprazole being a well known proton pump inhibitor has been shown to be able to prevent gastric and duodenal erosions in healthy volunteers during treatment with acetyl salicylic acid. Clinical studies have shown, that omeprazole heals gastric as well as duodenal ulcers as fast and effectively in patients on continuous NSAID treatment as in non-NSAID users (Walan A. Engl J Med 1989;320:69). These results have been the basis for an amendment to the dose recommendation for the use of omeprazole in healing of gastric and duodenal ulcers during continuous NSAID treatment approved by regulatory authorities in UK and Sweden.
Recent studies confirm, that omeprazole significantly reduces the risk of developing gastric ulcers, duodenal ulcers and also dyspeptic symptoms in patients on continuous NSAID treatment.
EP0 426 479 describes tablet compositions comprising a NSAID such as ibuprofen and a gastric acid inhibiting drug, such as cimetidin etc. No specific arrangement is taken to avoid degradation if the gastric acid inhibitor is an acid susceptible compound, such as a proton pump inhibitor.
In proposed therapies comprising NSAID(s) and an acid susceptible proton pump inhibitor the different active substances are administred separately. It is well known that patient compliance is a main factor in receiving a good result in medical treatments. Therefore, administration of two or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms comprising two or more different active substances combined in one fixed unit dosage form, preferably a tablet.
Some anti-ulcer drugs such as proton pump inhibitors are susceptible to degradation/transformation in acid reacting and neutral media as mentioned above. In respect of the stability properties, it is obvious that the one of the active substances being a proton pump inhibitor must be protected from contact with acidic gastric juice by an enteric coating layer. There are different enteric coating layered preparations of proton pump inhibitors described in the prior art, see for example U.S. Pat. No. 4,786,505 (AB Hxc3xa4ssle) comprising omeprazole.
There are problems to produce a fixed unit dosage form comprising a rather high amount of active substance. Active substances with different physical properties combined in the same preparation give further problems. Preparation of a multiple unit tableted dosage form arises specific problems when enteric coating layered pellets containing the acid susceptible proton pump inhibitor are compressed into tablets. If the enteric coating layer does not withstand the compression of the pellets into a tablet, the susceptible active substance will be destroyed upon administration by penetrating acidic gastric juice, i.e. the acid resistance of the enteric coating layer of the pellets will not be sufficient in the tablet after compression.
The present invention provides oral, fixed unit dosage forms, i.e. multiple unit tableted dosage forms, enteric coating layered tablets, multilayered tablets or capsules filled with more than one pharmaceutically active compound. The active compounds are preferably an acid susceptible proton pump inhibitor in combination with one or more NSAIDs and wherein at least the proton pump inhibitor is protected by an enteric coated layer. These new dosage forms will simplify the regimen and improve the patient compliance.